It is said that the history of anesthesia started from ether general anesthesia by a dentist E. G. T. Morton publicly in 1846. In 1884, 38 years later, local anesthesia started to be applied in a clinical setting in ophthalmology. As described above, the history of local anesthesia is shorter than that of general anesthesia. In 1885, being the next year, the local anesthesia also started to be applied to dental therapies. In accordance with its applications to a wider variety of surgeries, the local anesthesia has mainly been demanded for providing a long-term sustained action and strong local anesthesia, but is still a developing technology. An effect of the same local anesthetic agent is proportional to an amount of the local anesthetic agent to be used, and hence the use in a large amount also enhances the effect. However, because intoxication due to the use in a large amount causes a threat to life, the amount of the local anesthetic agent to be used is limited as a matter of course.
In view of the foregoing, in clinical practice, a local anesthetic agent having added thereto a composition for local anesthesia (mainly vasoconstriction) may be used in order to prolong the duration of a local anesthetic action and to enhance anesthesia. For example, dental therapies require strong local anesthesia to anesthetize the nerve at the tip of the root of a tooth embedded in the bone, and further require a long-term local anesthetic action to remove a wisdom tooth embedded in the bone. Thus, the local anesthetic agent having added thereto a composition for local anesthesia is generally used.
The composition for local anesthesia is added for the purposes such as: (1) enhancing a local anesthetic effect; (2) locally retaining a local anesthetic agent to prolong an anesthetic duration; (3) delaying the absorption of local anesthesia to prevent the appearance of intoxication; (4) reducing the amount of a local anesthetic agent to be used; and (5) suppressing bleeding from a surgical field to provide a sufficient visual field (see Dental anesthesiology, 6th edition, Chapter 4 Local anesthetic method). As described above, the composition for local anesthesia has various advantages in addition to the prolonged duration of action and the anesthesia enhancing action. At present, adrenalines (including adrenaline, epinephrine tartrate, and other catecholamines) and polypeptides such as felypressin are used as the composition for local anesthesia. Among ones which may be generally used, adrenaline or a salt thereof is most effective and is used frequently at a concentration of 2.73 to 7.6×10−5 M.
Adrenaline or a salt thereof serving as a vasoconstrictor at a concentration of 2.73 to 7.6×10−5 M is effective and hence is used as the composition for local anesthesia most frequently from the past up to the present. However, it has been reported that, in the case of administering a local anesthetic agent having added thereto a composition for local anesthesia including adrenaline or a salt thereof, adrenaline in the composition for local anesthesia acts on not only an injection site but also a systemic body, resulting in specific severe adverse effects such as an increase in blood pressure or an adverse influence on the heart. It is therefore necessary to carefully administer the local anesthetic agent to older people (local anesthetic agent: lidocaine hydrochloride-adrenaline injection, see package insert). Further, a local anesthetic agent having added thereto a vasoconstrictor including adrenaline or a salt thereof may exacerbate medical conditions of patients suffering from, for example, hypertension, arteriosclerosis, heart failure, hyperthyroid, and diabetes, and is hence contraindicated for use in those patients in principle (local anesthetic agent: lidocaine hydrochloride-adrenaline injection, see package insert). Further, from the viewpoint of drug interactions, when patients constantly take a β receptor blocker, a tricyclic antidepressant, a butyrophenone drug, an α receptor blocker, a digitalis preparation, quinidine, a β receptor agonist, an antidiabetic, or the like, the combined use should be undertaken with care (local anesthetic agent: lidocaine hydrochloride-adrenaline injection, see package insert).
A composition for local anesthesia as an alternative to adrenaline or a salt thereof is under development. Felypressin as a polypeptide is a composition for local anesthesia which is generally used except adrenaline but shows a lower efficacy than adrenaline or a salt thereof and is hence not frequently used. In addition, although it is said that acidic mucopolysaccharides, a cellulose derivative, maltosyl β-cyclodextrin, salicylic acid, an antihistamine agent, and the like each have such action, those have not yet been put to practical and general use (Patent Literatures 1 to 5). It is conceivable that any such substance alone lacks superiority enough to serve as an alternative to adrenaline or a salt thereof. Meanwhile, researches on compositions from the viewpoint of suppressing adverse effects by reducing the amount of adrenaline or a salt thereof have also been carried out, but also in this case, the compositions are not practical in terms of, for example, drug particularity and complexity (Patent Literatures 6 and 7).
There is a report that a local anesthetic action is enhanced by adding dexmedetomidine serving as an α2 receptor agonist as a novel composition for local anesthesia to a local anesthetic agent (Non Patent Literature 1). Further, there is given an aid for an anesthetic agent for pain control and neurologic inflammation as one of the fields which may be treated with an α-2 receptor agonist (α2 receptor agonist) (Patent Literature 8). A number of reports have demonstrated that the α2 receptor agonist as a preanesthetic medication has sedative and antianxiety actions and reduces the amount of an analgesic drug required in the perioperative period. For the local anesthetic agent, however, a composition for local anesthesia including adrenaline and an α2 receptor agonist has not been reported heretofore. Adrenaline is an agonist acting on both of an α1 receptor and an α2 receptor, whereas dexmedetomidine is an agonist highly selective for the α2 receptor. As for actions of an α1 receptor agonist and an α2 receptor agonist, the idea that the α1 receptor agonist gives an additive effect and the α2 receptor agonist reduces the effect in a sympathetic response (Starke K: α-Adrenoceptor subclassification.: Non Patent Literature 2) is general. Further, research on binding to receptors (Wright I K, et al.: Non Patent Literature 3) has demonstrated that the binding to the α1 receptor and the α2 receptor in large blood vessels is also additive or weakly counteracting. There is also a report that the preadministration of yohimbine serving as an α2 receptor antagonist had no influence on a local anesthesia enhancing action of adrenaline (Kippei Goto: Research on action mechanism of vasoconstrictor as local anesthetic action enhancing substance: Non Patent Literature 4).